Novel method stabilizing bupropion hydrochloride tablets

ABSTRACT

The present invention relates to a stable bupropion hydrochloride tablet and a method of stabilizing bupropion hydrochloride tablets, which also serves as an improved tabletting process for the preparation of sustained release bupropion hydrochloride tablets.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a stable bupropion hydrochloride tabletand a method of stabilizing bupropion hydrochloride tablets, which alsoserves as an improved tabletting process for the preparation ofsustained release bupropion hydrochloride tablets.

BACKGROUND OF THE INVENTION

Bupropion hydrochloride is a well-known antidepressant and anon-nicotine aid to smoking cessation. GLAXOSMITHKLINE sells it inUnited States as WELLBUTRIN® (bupropion hydrochloride immediate releasetablets), WELLBUTRIN® SR and ZYBAN® SR (bupropion hydrochloridesustained release tablets). Bupropion hydrochloride also has utility asan anticholesterol agent, in suppressing prolactin secretion, inpreventing functional impairment and drowsiness seen upon administrationof benzodiazepine, in the treatment of minimal brain dysfunction,tardive dyskinesia, impaired mental alertness upon ingestion of ethanoland psychosexual dysfunction.

Bupropion hydrochloride is a water-soluble, crystalline solid, which ishighly hygroscopic and susceptible to decomposition. Because of thedrug's instability, researchers working in this field have tried anumber of different approaches to improve the storage stability of thedrug in the formulation. U.S. Pat. Nos. 5,358,970; 5,763,493; 5,731,000;5,427,798; 5,968,553; 5,541,231; and 6,242,496 variously disclose theuse of organic acids, carboxylic acids, dicarboxylic acids, inorganicacids, acid salts of an amino acids, sodium metabisulfite, and sodiumbisulfate as stabilizers for bupropion compositions. A potentialdisadvantage of using acidic materials in pharmaceutical formulations,such as those disclosed above, is the possible need to provide costlyproduction procedures and equipment.

For example, U.S. Pat. No. 5,358,970, which is incorporated herein inits entirety by reference, states that suitable stabilizers are thosewhich have an aqueous solution pH of about 0.9 to about 4 at an aqueoussolution concentration of about 6% w/w and are a solid or liquid at 30°C. The '970 patent further states that specific suitable stabilizersthat meet the pH range and are therefore useful include: L-cysteinehydrochloride, glycine hydrochloride, ascorbic acid, malic acid, sodiummetabisulfite, isoascorbic acid, citric acid, tartaric acid, L-cystinedihydrochloride. L-cysteine hydrochloride and glycine hydrochloride.

U.S. Pat. No. 5,763,493, which is incorporated herein in its entirety byreference, states the stabilizer is selected from an organic acid, acarboxylic acid other than ascorbic acid and isoascorbic acid, an acidsalt of an amino acid, and sodium metabisulphite, and further statesthat the preferred pH of the aqueous solution of the stabilizer is 0.9to about 2 and most preferably 1.

U.S. Pat. No. 5,731,000, which is incorporated herein in its entirety byreference, describes suitable stabilizers as including organic acids,carboxylic acids, acid salts of amino acids and sodium metabisulphiteand further states that preferably, the acid salts of amino acids arehydrochloride salts such as cysteine hydrochloride, glycinehydrochloride or cystine dihydrochloride. Other preferred examples ofstabilizers are described as including ascorbic acid, malic acid,isoascorbic acid, citric acid and tartaric acid, and that L-cysteinehydrochloride and glycine hydrochloride are the most preferredstabilizers.

U.S. Pat. No. 5,968,553, which is incorporated herein in its entirety byreference, characterizes suitable stabilizers as being inorganic acidshaving an aqueous solution pH of from about 0.5 to about 4.0 at aconcentration of about 0.31% w/w. The '553 patent states that suitablestabilizers include inorganic acids meeting the above criteria andinclude hydrochloric acid, phosphoric acid, nitric acid, and sulfuricacid, or combinations thereof. Hydrochloric acid is described as being apreferred stabilizer.

U.S. Pat. No. 6,242,496, which is incorporated herein in its entirety byreference, describes the stabilizers as including dicarboxylic acidsincluding oxalic, succinic, adipic, fumaric and phthalic acids, orcombinations thereof, and that fumaric acid is a preferred stabilizer.

U.S. Pat. No. 5,427,798 describes formulations in which drug release isachieved in a controlled manner by varying the surface area to volumeratio of the tablet. However, U.S. Pat. No. 5,427,798 relies on theinclusion of acids to stabilize the bupropion hydrochloride.

U.S. Pat. No. 6,306,436 discloses stabilized bupropion hydrochloridepharmaceutical compositions that are free of added acid and provide forsustained release of bupropion hydrochloride. Stabilization is achievedby using particulate bupropion hydrochloride, which is coated with amembrane coating or by large size bupropion crystals. Although avoidingthe potential disadvantages of using an acid, a potential disadvantageof using the disclosure of U.S. Pat. No. 6,306,436 is that a drugparticle coating may be an expensive and time-consuming process.

U.S. Pat. No. 6,238,697 describes methods and formulations for makingextended release bupropion hydrochloride tablets using a directcompression method. In the disclosed methods and formulations, tabletsare formed that combine bupropion hydrochloride, binders, fillers,glidants and lubricants and processing under low shear conditions thatresult in hard, chip-resistant tablets that exhibit improvedcohesiveness and are easily and reproducibly formed without adhering tothe compression punches. The disclosed methods and formulations employthe use of sodium sulfite or potassium metabisulfite to improve thestability of bupropion hydrochloride.

Direct compression requires the use of specific excipients of particularsize and density to avoid the problems of segregation and non-uniformcontent of the drug product. Requiring a process to use excipients of aspecific particle size and density range, however, adds to costs andmakes the process less robust. Moreover, the success of the directcompression process further depends on bulk density, tap density andparticle size distribution of the drug.

Most of the prior art researchers have used wet granulation methods toprepare bupropion hydrochloride immediate release or sustained releasetablets.

Wet granulation provides better content uniformity, but is not advisablefor active ingredients, such as bupropion hydrochloride, that arehygroscopic and susceptible to decomposition. Moreover, polymers,especially the hydrophilic polymers typically usually used in achievingextended release, interact with the aqueous system making wetgranulation a cumbersome process. The wet granulation process withhydrophilic polymers may also result in variable release characteristicsdepending on the degree of hydration of the polymer. Even the fluidvolume of the granulating agent and granulation time may also affect therelease characteristics. Further, use of an organic solvent in theprocess leads to the problem of residual solvents and extra cost formaintaining the environmental standards inside the plant and in theoutside surroundings.

Hence, there is a need for not only a better stabilization method, butalso for an improved tabletting process.

SUMMARY OF THE INVENTION

In one general aspect there is provided a stable bupropion hydrochloridetablet. The tablet is free of stabilizer and contains at least about 80%of undegraded bupropion hydrochloride after storage for two months at40° C. and 75% relative humidity.

Embodiments of the tablet may include one or more of the followingfeatures. For example, the tablet may be a sustained release tablet. Thetablet may include bupropion hydrochloride, one or more release ratecontrolling polymers, and one or more diluents, binders, lubricants,glidants and coloring agents. The release rate controlling polymers mayinclude one or more of cellulose derivatives, acrylates,polyvinlyacetate/povidone mixtures, polyethylene oxides, starches andtheir derivatives, gums, alginates, carbohydrate based polymers,polysaccharide, and combinations thereof.

The cellulose derivative may be one or more of ethyl cellulose,methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, hydroxypropyl methylcellulose, sodiumcarboxymethylcellulose, and combinations thereof. The cellulosederivative may be hydroxypropyl cellulose. The acrylate may be one ormore of carbomer, polycarbophil, and EUDRAGIT®. The carbomer may includeone or more of Carbopol®-971 P, 974 P, and 934 P.

The binder may be one or more of starch, gelatin, highly dispersedsilica, mannitol, lactose, polyethylene glycol, polyvinylpyrrolidone,cross-linked polyvinylpyrrolidone, cross-linked carboxymethyl cellulose,hydroxypropyl methylcellulose, hydroxypropyl cellulose and natural andsynthetic gums. The diluent may be microcrystalline cellulose. Thelubricant may be stearic acid.

In another general aspect, there is provided a method of stabilizingbupropion hydrochloride tablets by using a dry granulation process. Thedry granulation process includes a) blending bupropion hydrochloride andone or more pharmaceutically acceptable excipient(s), b) compacting orslugging the material of step (a), c) sizing the compacted or sluggedmaterial of step (b) into granules, and d) compressing the granules ofstep (c).

The method may include one or more of the following features. Forexample, the tablet may contain at least about 80% of undegradedbupropion hydrochloride after storage for two months at 40° C. and 75%relative humidity.

Step (b) may be compaction. The compaction may include using a rollercompactor. Step (c) may be milling. The method may further includelubricating the sized granules of step (c) before compressing thegranules. The method may still further include coating the tablet aftercompressing the granules.

The one or more pharmaceutically acceptable excipients may be one ormore of release rate controlling polymers, diluents, binders,lubricants, glidants, and coloring agents. The release rate controllingpolymers may be one or more of cellulose derivatives, acrylates,polyvinlyacetate/povidone mixtures, polyethylene oxides, starches andtheir derivatives, gums, alginates, carbohydrate based polymers,polysaccharide, and combinations thereof. The cellulose derivative maybe one or more of ethyl cellulose, methylcellulose,hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropyl methylcellulose, sodium carboxymethylcellulose, andcombinations thereof. The cellulose derivative may be hydroxypropylcellulose. The acrylate may be one or more of carbomer, polycarbophil,and EUDRAGIT®. The carbomer may be one or more of Carbopol®-971P, 974Pand 934P.

The binder may be one or more of from starch, gelatin, highly dispersedsilica, mannitol, lactose, polyethylene glycol, polyvinylpyrrolidone,cross-linked polyvinylpyrrolidone, cross-linked carboxymethyl cellulose,hydroxypropyl methylcellulose, hydroxypropyl cellulose, and natural orsynthetic gums. The diluent may be microcrystalline cellulose. Thelubricant may be stearic acid. The bupropion hydrochloride tablets maybe free of stabilizer.

In another general aspect, a method of one or both of treatingdepression and providing smoking cessation is provided. The methodincludes providing bupropion hydrochloride in a dosage form that is freeof stabilizer and contains at least about 80% of undegraded bupropionhydrochloride after storage for two months at 40° C. and 75% relativehumidity.

Embodiments of the method may include any one or more of the featuresdescribed above. For example, the dosage form may be produced using adry granulation process that includes (a) blending bupropionhydrochloride and one or more pharmaceutically acceptable excipients,(b) either compacting or slugging the blend of step (a), sizing thecompacted or slugged material of step (b) into granules, and (d)compressing the granules of step (c).

The methods, processes, and formulations described herein may provideone or more of the following features. For example, the method is simpleand produces tablets having good stability during storage and desiredsustained release characteristics. The method can avoid the use of anacid stabilizer, coated bupropion hydrochloride particles, and largersized bupropion hydrochloride crystals, thereby resulting in reducedcosts. The method can also eliminate the use of organic solvent duringwet granulation. Therefore, the problem of residual solvent isnonexistent. The method can also eliminate the variability in the degreeof hydration of hydrophilic polymers and its consequent effect onrelease characteristics.

The method can provide granules with consistent hardness and increaseddensity. Granules for high-speed tabletting or encapsulation areproduced with reproducible granule size distribution. Less variation inparticle size distribution reduces the need for reprocessing fines. Theprocess can provide a good reprocessing potential as the compacts orslugs and tablets can be crushed into powder and re-compacted to makethe tablets without affecting drug release profiles.

The details of one or more embodiments of the invention are set forth inthe accompanying drawings and the description below. Other features,objects, and advantages of the invention will be apparent from thedescription and the claims.

DETAILED DESCRIPTION OF THE INVENTION

The inventors have discovered that stable bupropion hydrochloridetablets can be prepared by a dry granulation process without having toadd any stabilizer. The inventors also have discovered that the processof dry granulation further serves as an improved tabletting process forthe preparation of sustained release bupropion hydrochloride tablets.Therefore, the method described herein not only stabilizes bupropionhydrochloride without having to use the acid stabilizer, coatedbupropion hydrochloride particles, or larger sized bupropionhydrochloride crystals of the prior art researchers, but also provides abetter tabletting process for the preparation of sustained releasetablets.

Therefore, one aspect of the present invention is a stable bupropionhydrochloride tablet in which the tablet is free of any stabilizer andcontains at least about 80% of undegraded bupropion hydrochloride afterstorage for two months at 40° C. and 75% relative humidity. Anotheraspect is a method for preparing a stable bupropion hydrochloride tabletin which the tablet is prepared by a dry granulation process and thetablet contains at least about 80% of undegraded bupropion hydrochlorideafter storage for two months at 40° C. and 75% relative humidity.Another aspect is a method for preparing a stable sustained releasebupropion hydrochloride tablet by a dry granulation process and thetablet contains at least about 80% of undegraded bupropion hydrochlorideafter storage for two months at 40° C. and 75% relative humidity.

Another aspect is a stable bupropion hydrochloride sustained releasetablet that is free of any stabilizer and contains at least about 80% ofundegraded bupropion hydrochloride after storage for two months at 40°C. and 75% relative humidity. Examples of stabilizers include sodiumsulfite and potassium metabisulfite, as well as acids, such as organicacids, carboxylic acids, dicarboxylic acids, inorganic acids, acid saltsof an amino acids, sodium metabisulfite, and sodium bisulfate. Asdescribed above, a stabilizer can be characterized by using an aqueoussolution pH of about 0.9 to about 4 at an aqueous solution concentrationof about 6% w/w and are a solid or liquid at 30° C. Stabilizers thatmeet that pH range include: L-cysteine hydrochloride, glycinehydrochloride, ascorbic acid, malic acid, sodium metabisulfite,isoascorbic acid, citric acid, tartaric acid, L-cystine dihydrochloride,L-cysteine hydrochloride and glycine hydrochloride. Other stabilizersinclude organic acids, carboxylic acids, and an acid salt of an aminoacid. Acid salts of amino acids include hydrochloride salts such ascysteine hydrochloride, glycine hydrochloride or cystinedihydrochloride. Other stabilizers include dicarboxylic acids includingoxalic, succinic, adipic, fumaric and phthalic acids.

The dry granulation process generally includes the steps of:

-   a) blending bupropion hydrochloride and other pharmaceutically    acceptable excipient(s),-   b) compacting or slugging,-   c) sizing the compacted or slugged material of step (b) into    granules, and-   d) compressing the granules of step (c) to form tablets.    Again, the process is free of stabilizers.

The term “bupropion hydrochloride” is used to refer to the hydrochloridesalt of m-chloro-α-(t-butylamino)propiophenone.

The pharmaceutically acceptable excipients may be selected from amongstone or more of release rate controlling polymers, diluents, binders,lubricants, glidants, and coloring agents which are compatible withbupropion hydrochloride and which would help in optimizing tabletrobustness and drug dissolution from the tablet.

Release rate-controlling polymers may be selected from anypharmaceutically acceptable excipients that can control the rate ofrelease of the active ingredient. For example, such releaserate-controlling polymers can be selected from the group that includescellulose derivatives, acrylates, polyvinlyacetate/povidone mixture,polyethylene oxides, starch and their derivatives, gums, alginates,carbohydrate based polymers, polysaccharides, and combinations thereof.

Cellulose derivative can be selected, for example, from one or more ofthe group that includes ethyl cellulose, methylcellulose,hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropyl methylcellulose, and sodium carboxymethylcellulose havingdifferent degrees of substitution or viscosities and molecular weights.These release rate-controlling polymers can be used alone or incombination. Various degrees of substitution and/or different molecularweights corresponding to a different degree of viscosity can be used assuitable cellulose based rate-controlling polymers.

The term “acrylates” is used to describe linear, non-crosslinkedcopolymers that contain combinations of acrylic acid, methacrylic acidand their simple esters. Acrylates can be selected from the group thatincludes carbomer, polycarbophil and EUDRAGIT®.

The name “Carbomer” is used to describe high molecular weightcross-linked homopolymers of acrylic acid. Carbomers commerciallyavailable under the trademark Carbopol® may be selected fromCarbopol®-934P, 971P or 974P. Methacrylic acid polymers and copolymerscommercially available under the trademark EUDRAGIT® s are particularlysuitable.

The rate controlling polymer or polymers can be used in a concentrationof approximately 5% to approximately 60% of the tablet weight dependingon the polymer or polymers used. The use of hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose,polyvinlyacetate/povidone mixture or Carbopol®-971P is particularlysuitable. These polymers swell to form a hydrophilic matrix system,which controls the release of bupropion hydrochloride. The tablethydrates on wetting with aqueous fluids and the hydrophilic polymersform a gel layer. Due to permeation of aqueous fluid into the tablet thethickness of gel layer is increased, and bupropion hydrochloridediffuses slowly out of the gel layer. Slow erosion of the swollen gelmay also contribute to drug release.

Diluents may be selected from one or more of any suitablepharmaceutically acceptable excipient that gives bulk to the compositionand improves compressibility. For example, diluents may be selected fromthe group that includes starch, microcrystalline cellulose, lactose,glucose, mannitol, alginates, alkali earth metal salts, dicalciumphosphate, glyceryl monostearate, and polyethylene glycols.Microcrystalline cellulose is particularly suitable.

Binders may be selected from one or more of any pharmaceuticallyacceptable excipients that have cohesive properties to act as a binder.For example, suitable excipients include starch, gelatin, highlydispersed silica, mannitol, lactose, polyethylene glycol,polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, cross-linkedcarboxymethyl cellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, and natural or synthetic gums.

Lubricants may be selected, for example, from one or more of talc,stearic acid, magnesium stearate, other alkali earth metal stearate likecalcium, zinc etc., sodium lauryl sulphate, hydrogenated vegetable oil,sodium benzoate, sodium stearyl fumarate, glyceryl monostearate, and PEG4000.

Glidants may be selected, for example, from colloidal silicon dioxide,talc, and other suitable glidants.

As described above, the ingredients are blended and the blend iscompacted by roller compaction. The compactor can have rollers andpowder transport screws of different designs. Alternatively, this blendmay instead be compressed to make slugs. Whether the blend is compactedor slugged (i.e., compressed to make slugs), either process can be usedwith bupropion hydrochloride alone or with one or more rate controllingpolymers and/or excipient(s).

Next, the compacted or slugged material is sized by a suitable machine,such as an oscillating granulator, Multimill, and/or Fitzmill and sievedinto the desired granule size.

As an optional step, the granules that are either too large or too smallare recycled and combined with an original powder mix and passed throughthe roller compactor or tabletting machine. Normally 30-70% of coarsegranules (i.e., retained on a 44-mesh sieve and passed through an18-mesh sieve) are preferred and are usually achieved in a singlecompaction cycle.

These granules are optionally lubricated with the lubricant and arecompressed to form tablets. These tablets optionally may be given acoating to enhance the aesthetic appeal. Optionally, these granules canbe capsulated into the hard gelatin capsules.

The following examples are provided to enable one of ordinary skill inthe art to prepare dosage forms of the invention and should not beconstrued as limiting the scope of the invention.

EXAMPLES 1-4

Bupropion hydrochloride 150-mg formulations Weight (mg) per tabletIngredient Example 1 Example 2 Example 3 Example 4 Bupropionhydrochloride 150.00 150.00 150.00 150.00 Hydroxypropyl cellulose- 63.00— — 31.5 M Polyvinlyacetate/ — 63.00 — — Povidone mixture Carbopol ®971P — — 63.00 31.5 Microcrystalline 200.00 200.00 200.00 200.00cellulose Stearic acid 3.2 3.2 3.2 3.2 Total 416.00 416.00 416.00 416.00

The above bupropion hydrochloride formulations were prepared using thefollowing process:

-   1. Bupropion Hydrochloride, microcrystalline cellulose, and the rate    controlling polymers were sifted through a 44 BSS sieve and    lubricated with stearic acid (half of the total quantity),-   2. The blend of step 1 was compacted using a roller compacter,-   3. The compacts of step 2 were sized through an oscillating    granulator and sifted through an 18 BSS sieve.-   4. The fines obtained were recycled to achieve the desired ratio of    coarse and fines.-   5. The granules of step 4 were lubricated with the remaining    quantity of stearic acid and compressed into tablets.

The stability of the tablets prepared as per the composition and processof Examples 1-4 at 40° C. and 75% RH is given in Table-1. TABLE 1Comparative Stability of Bupropion Hydrochloride Tablets Prepared as Perthe Composition of Examples 1-4 and Commercially Available BupropionHydrochloride Tablets (WELLBUTRIN SR ® tablets). % bupropionhydrochloride EXAMPLES Stability conditions 1 2 3 4 WELLBUTRIN SR ®Initial 98.5 96 102 101.8 105.3 1 month at 40° C. 97.0 95 101.3 — 95.1and 75% RH 2 months at 40° C. 93.6 90.0 102.4 104.5 89.0 and 75% RHRH = Relative Humidity*of added quantity

The dissolution profile of the tablets prepared as per the compositionand process of Examples 1, 3, and 4 is given in Table-2. TABLE 2Dissolution Profiles of Bupropion Hydrochloride (150 mg) Formulations(in distilled water 900 ml at 50 rpm using USP-2 apparatus). Time %bupropion hydrochloride dissolved (hrs) Example 1 Example 3 Example 40.5 22 19 20 1 34 26 29 2 48 37 41 4 64 53 59 6 73 67 69 8 78 72 72

The above data in Tables 1 and 2 clearly indicate that the granulationboth stabilizes bupropion hydrochloride tablets without any stabilizerand also serves as an improved tabletting process for the preparation ofsustained release bupropion hydrochloride tablets.

While several particular forms of the invention have been illustratedand described, it will be apparent that various modifications andcombinations of the invention detailed in the text and claims can bemade without departing from the spirit and scope of the invention. Forexample, the dosage formulations described herein can be prescribed forone or more of the following uses: treating depression, providingsmoking cessation, as an anticholesterol agent, in suppressing prolactinsecretion, in preventing functional impairment and drowsiness seen uponadministration of benzodiazepine, in the treatment of minimal braindysfunction, tardive dyskinesia, impaired mental alertness uponingestion of ethanol and psychosexual dysfunction. Moreover, it iscontemplated that any single feature or any combination of optionalfeatures of the inventive variations described herein may bespecifically excluded from the claimed invention and be so described asa negative invention. Accordingly, it is not intended that the inventionbe limited, except as by the appended claims.

1. A stable bupropion hydrochloride tablet, wherein the tablet is freeof stabilizer and contains at least about 80% of undegraded bupropionhydrochloride after storage for two months at 40° C. and 75% relativehumidity.
 2. The tablet according to claim 1, wherein the tablet is asustained release tablet.
 3. The tablet according to claim 1, whereinthe tablet comprises bupropion hydrochloride, one or more release ratecontrolling polymers, and one or more diluents, binders, lubricants,glidants and coloring agents.
 4. The tablet according to claim 3,wherein the release rate controlling polymers comprises one or more ofcellulose derivatives, acrylates, polyvinlyacetate/povidone mixtures,polyethylene oxides, starches and their derivatives, gums, alginates,carbohydrate based polymers, polysaccharide, and combinations thereof.5. The tablet according to claim 4, wherein the cellulose derivativecomprises one or more of ethyl cellulose, methylcellulose,hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropyl methylcellulose, sodium carboxymethylcellulose, andcombinations thereof.
 6. The tablet according to claim 5, wherein thecellulose derivative comprises hydroxypropyl cellulose.
 7. The tabletaccording to claim 4, wherein the acrylate comprises one or more ofcarbomer, polycarbophil, and EUDRAGIT®.
 8. The tablet according to claim7, wherein the carbomer comprises one or more of Carbopol®-971 P, 974 P,and 934 P.
 9. The tablet according to claim 3, wherein the bindercomprises one or more of starch, gelatin, highly dispersed silica,mannitol, lactose, polyethylene glycol, polyvinylpyrrolidone,cross-linked polyvinylpyrrolidone, cross-linked carboxymethyl cellulose,hydroxypropyl methylcellulose, hydroxypropyl cellulose and natural, andsynthetic gums.
 10. The tablet according to claim 3, wherein the diluentcomprises microcrystalline cellulose.
 11. The tablet according to claim3, wherein the lubricant comprises stearic acid.
 12. A method ofstabilizing bupropion hydrochloride tablets using a dry granulationprocess, the dry granulation process comprising: a) blending bupropionhydrochloride and one or more pharmaceutically acceptable excipient(s),b) compacting or slugging the material of step (a), c) sizing thecompacted or slugged material of step (b) into granules, and d)compressing the granules of step (c).
 13. The method according to claim12, wherein the tablet contains at least about 80% of undegradedbupropion hydrochloride after storage for two months at 40° C. and 75%relative humidity.
 14. The method according to claim 12, wherein step(b) comprises compaction.
 15. The method according to claim 14, whereinthe compaction comprises using a roller compactor.
 16. The methodaccording to claim 12, wherein step (c) comprises milling.
 17. Themethod according to claim 12, further comprising lubricating the sizedgranules of step (c) before compressing the granules.
 18. The methodaccording to claim 12, further comprising coating the tablet aftercompressing the granules.
 19. The method according to claim 12, whereinthe one or more pharmaceutically acceptable excipients comprise one ormore of release rate controlling polymers, diluents, binders,lubricants, glidants, and coloring agents.
 20. The method according toclaim 19, wherein the release rate controlling polymers comprise one ormore of cellulose derivatives, acrylates, polyvinlyacetate/povidonemixtures, polyethylene oxides, starches and their derivatives, gums,alginates, carbohydrate based polymers, polysaccharide, and combinationsthereof.
 21. The method according to claim 20, wherein the cellulosederivative comprises one or more of ethyl cellulose, methylcellulose,hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropyl methylcellulose, sodium carboxymethylcellulose, andcombinations thereof.
 22. The method according to claim 21, wherein thecellulose derivative comprises hydroxypropyl cellulose.
 23. The methodaccording to claim 20, wherein the acrylate comprises one or more ofcarbomer, polycarbophil, and EUDRAGIT®.
 24. The method according toclaim 23, wherein carbomer comprises one or more of Carbopol®-971 P, 974P and 934 P.
 25. The method according to claim 19, wherein the bindercomprises one or more of from starch, gelatin, highly dispersed silica,mannitol, lactose, polyethylene glycol, polyvinylpyrrolidone,cross-linked polyvinylpyrrolidone, cross-linked carboxymethyl cellulose,hydroxypropyl methylcellulose, hydroxypropyl cellulose, and natural orsynthetic gums.
 26. The method according to claim 19, wherein thediluent comprises microcrystalline cellulose.
 27. The method accordingto claim 19, wherein the lubricant comprises stearic acid.
 28. Themethod according to claim 12, wherein the bupropion hydrochloridetablets are free of stabilizer.
 29. A method of one or both of treatingdepression and providing smoking cessation, the method comprising:providing bupropion hydrochloride in a dosage form, wherein the dosageform is free of stabilizer and contains at least about 80% of undegradedbupropion hydrochloride after storage for two months at 40° C. and 75%relative humidity.
 30. The method of claim 29, wherein the dosage formis produced using a dry granulation process, the dry granulation processcomprising (a) blending bupropion hydrochloride and one or morepharmaceutically acceptable excipients, (b) either compacting orslugging the blend of step (a), sizing the compacted or slugged materialof step (b) into granules, and (d) compressing the granules of step (c).